Departments of Medical Oncology and Laboratory of Preclinical Investigation, Translational Research Department;
Genetics, Hospital, Institut Curie;
Clin Cancer Res. 2014 Aug 15;20(16):4314-25. doi: 10.1158/1078-0432.CCR-13-3230. Epub 2014 Jun 19.
Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.
Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.
HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.
PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.
患有腔面型乳腺癌（LBC）的患者往往会随着时间的推移而对内分泌治疗产生耐药性。我们研究了与 LBC 患者来源的异种移植物获得性激素抵抗相关的分子变化。
对两种 LBC 异种移植物（HBCx22 和 HBCx34）进行了不同的内分泌治疗（ET），以获得对他莫昔芬（TamR）和卵巢切除术（OvaR）具有获得性耐药的异种移植物。通过 Western blot 分析和 IHC 分析来分析 PI3K 通路的激活，并在体内研究了对 ET 联合依维莫司的反应。通过 RT-PCR 和 Affymetrix 芯片进行基因表达分析。
HBCx22 TamR 异种移植物对多种激素治疗具有交叉耐药性，而 HBCx22 OvaR 和 HBCx34 TamR 则表现出特定的治疗耐药性谱。在亲本和耐药异种移植物中，PI3K 通路均被激活，但在 TamR 异种移植物中加入依维莫司并不能恢复对他莫昔芬的反应。相反，在 HBCx34 TamR 中，氟维司群和依维莫司的联合使用在体内诱导了肿瘤消退，我们发现雌激素受体（ER）和 PI3K 通路之间存在串扰。在 TamR 和 OvaR 肿瘤中，几种 ER 控制的基因和 ER 共调节剂的表达均发生了显著变化，表明 ER 转录活性受损。与激素耐药相关的表达变化在肿瘤和治疗方面均具有特异性，并富集了参与细胞生长、细胞死亡和细胞存活的基因。
对内分泌治疗产生获得性耐药的 LBC 的 PDX 模型表现出对内分泌治疗的耐药表型多样性很大，与 ER 介导的基因转录的特定失调有关。这些模型为开发抗癌疗法提供了工具，并可研究在药物干预过程中出现的耐药性动态。Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.
